PATHOPHYSIOLOGY/FUNCTIONAL SIGNIFICANCE OF WHITE MATTER SIGNAL HYPERINTENSITIES

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The objective of this multi-disciplinary prospective longitudinal study is to elucidate the pathophysiologic and functional significance of white matter signal hyperintensities (WMSH), a highly prevalent funding in brain MRI of normal and demented elderly persons. Evidence for two alternative pathophysiologic models will be examined: 1) WMSH are caused by chronic hypoperfusion of the deep white matter vs. 2) WMSH represent secondary demyelination that results from primary neuronal or axonal loss. A new visual-tactile motor reaction time paradigm has been developed to specifically test a neuroanatomical model for the functional significance of WMSH: namely, that WMSH causes slowing in responses that requires integration of sensory modalities across a distributed network. Four groups of 32 subjects each (n=128) will studied using a longitudinal repeated-measures design. The two major subgroups are comprised of normal elderly persons (CDR 0) and patients with cognitive impairment (CDR 0.5, 1 or 2). Each subgroup is further divided according to the severity of WMSH (mild vs moderate or severe). At baseline, the experimental reaction time paradigm, as well as volumetric studies of WMSH and grey matter will be performed for all subjects. Cerebral blood flow, glucose metabolism in areas of WMSH will be obtained using coregistered position emission tomography (PET) and MRI for a subset of patients with mild or severe WMSH severity. MRI studies, reaction time testing and PET will be repeated after 18 month intervals. Regional quantitative studies of white matter will be performed to test whether the pattern of demyelination corresponds better with the pattern of vascular perfusion or neuronal degeneration. Based upon regional patterns of selective vulnerability, we anticipate that patients with mild so moderate AD, as well as VaD, will be able to perform the visual-tactile motor paradigm. A longitudinal design has been chosen to clarify the temporal relationship between diminished cerebral blood flow and metabolism and to control for individual differences in the experimental variables. Thus, this study is designed to clarify the clinical importance and pathophysiology of WMSH in both AD and VaD.